There is enormous interest in studying HIV to improve the treatment for the AIDS pandemic. As study of the pathogen enters its 4th decade, HIV infection is becoming one of the best-studied biological systems. HIV infection of a human host can be considered a large complex system like the transportation, Internet, social, and economic systems we interact with daily. We contend that like the aforementioned macroscopic systems, we should begin to integrate information and develop tools for presenting the information to facilitate the study of HIV as a system, rather than a collection of segregated microdomains. To begin addressing one aspect of this issue, our laboratory has built HIVToolbox, a database about HIV proteins and an open-access web system that displays this information in a unified view to facilitate the study of HIV protein sequence, structure, and function; weblink: [http://hivtoolbox.bio-toolkit.com]. This integrated, interactive HIVToolbox system allows visual mining of relationships that are not readily revealed by other approaches where data is not integrated as well. This approach is useful for generating hypotheses, experimental design, and interpretation of experiments. HIVToolbox is the only website we know of that readily integrates data and coordinates display of sequence, structure, function, and conservation in a unified interface. HIVToolbox has already reached a wide audience with ~100,000 hits in the last 1.5 years. Here, we propose a significant expansion of the functionality of by implementing new approaches for using sequence, structural, function, and conservation information in HIVToolbox. The new HIVToolbox will also enabling comparison of drug binding sites with drug resistance mutations as an aid to consider drug resistance in ARV drug design. We will also generate a public HIV ontology that can be used for HIV bioinformatics research and connecting HIV research with other fields. This approach to data structure and presentation can also serve as a model for studying other important aspects of human health and disease.